title: Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function.
abstract: We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib in vivo, we established luciferase-labeled ACHN(Luc)  cells derived from papillary RCC. Mice in which ACHN(Luc)  cells had been transplanted into the left ventricle to establish bone metastases were treated orally with 40 mg/kg/day sunitinib or vehicle control for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, 16 patients with metastatic RCC were treated with sunitinib, and serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM-1 μM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN(Luc) ). Sunitinib prevented the growth of ACHN(Luc)  RCC cells in the bone metastatic mouse model. The number of osteoclasts in sunitinib-treated mice was significantly less than that in control mice. Serum and urine levels of NTx in patients with metastatic RCC declined significantly during the first 4 weeks of sunitinib treatment (p = 0.027). Sunitinib is a potent anticancer agent for RCC bone metastases, at least for papillary RCC.
authors.affiliation: Department of Urology, Akita University School of Medicine, Akita, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Shintaro
authors.initials: S
authors.lastname: Narita
authors.forename: Yohei
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.forename: Iwao
authors.initials: I
authors.lastname: Fukui
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010010:Osteoclasts / Q000187:drug effects*; D010455:Peptides / Q000097:blood / Q000652:urine; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D024042:Collagen Type I; D007211:Indoles; D010455:Peptides; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C052929:collagen type I trimeric cross-linked peptide; D016173:Macrophage Colony-Stimulating Factor; D000077210:Sunitinib